Angiogenesis is a key step in the progression of neoplasia from benign lesions to life-threatening disease. The central theme of this project is that the integration of knowledge from the molecular, cellular and tissue morphological levels will lead to a detailed understanding of the spatial and temporal regulation of angiogenesis in neonatal, normal adult and tumor settings. Subproject 1 will characterize blood vessels in normal or neoplastic tissue that form in the presence of various cytokines and inhibitors either alone or in combination. This project will also compare the gene expression of endothelium from neonatal, adult and VEGF-A overexpressing tissue. Subproject 2 seeks to characterize VEGF-A-mediated signaling pathways downstream of KDR/Flk-1 and Flt-1 and evaluate the role of these pathways in normal and tumor-induced angiogenesis. Subproject 3 will define the role of PlGF for vascularization of normal skin as well as during inflammation, carcinogenesis, experimental tumor growth, metastasis and angiogenesis. Subproject 4 seeks to characterize the multiprotein complex that functions as a receptor for thrombospondin-1 (TSP-1) on endothelial cells and determine the signaling pathways that mediate TSP-1-induced apoptosis. Core A (Administrative Support) will oversee and coordinate the scientific, fiscal and regulatory operations of the program. Core B (Morphology Support) will provide expertise in electron microscopy, in situ hybridization and confocal microscopy to the program. Core C (Cell Biology Support) will prepare and supply various types of well-characterized and standardized endothelial cells. Core D (Genomics Support) will perform the gene profiling studies and will provide bioinformatics support for data analysis and mining. Taken together, the scientific interactions, collaborations and exchange of reagents and expertise afforded by this Program Project will lead to a comprehensive understanding of the molecular, cellular and morphological basis of angiogenesis.